EP0697406A1 - Process for the preparation of polychloropyrimidines from polyhydroxypyrimidines - Google Patents

Abstract

Prepn. of polychloropyrimidines (I) involves reacting polyhydroxypyrimidines (II) with excess phosphorus oxychloride in presence of a tert. amine (TA). The novelty is that the reaction mixt. is treated by: (i) adding, per OH gp. replaced by Cl, 0.75-1.5 mol PCl3 and 0.7-1.4 mol chlorine, such that an excess of PCl3 over Cl2 is always present; (ii) successively distilling off PCl3, POCl3 and the obtd. (I) in a column under reduced pressure; (iii) treating the distn. residue with a strong base; (iv) further distilling under reduced pressure; and (v) recovering TA as the upper phase of the 2-phase distillate.

Description

The present invention relates to an improved process for the preparation of polychloropyrimidines, in particular 4,6-dichloropyrimidine from 4,6-dihydroxypyrimidine and from 2,4,6-trichloropyrimidine from barbituric acid.

Polychloropryimidines are intermediates for the production of crop protection agents and dyes.

In known processes for the preparation of 4,6-dichloropyrimidine, 4,6-dihydroxypyrimidine is mixed with phosphorus oxychloride and dimethylaniline or pyridine (see J. Chem. Soc. 1943 , 574; J. Chem. Soc. 1951 , 2214; Bull. Soc. Chim. France 1959 , 741 and Khim.-Pharm. Zhurnal 8 (12), 28 (1974) - English translation p. 741).

For working up, excess phosphorus oxychloride is first drawn off and then the residue is either discharged onto ice and the product is obtained by extraction and crystallization or is subjected to sublimation, in which the product is obtained as a sublimate. A disadvantage of this process is that dimethylaniline or pyridine are used in large amounts, but they can only be recovered and reused with considerable effort. In addition, the yields (maximum 81.1% of theory) are still in need of improvement. Finally, an aqueous workup is very complex because of the disposal of the waste water formed and the handling of extractants. Working up by sublimation is also very complex on a technical scale, for example with regard to the apparatus to be used and the hygiene requirements to remove the product from the sublimator.

Own attempts to make the known processes more advantageous by using smaller amounts of dimethylaniline failed because the yield of 4,6-dichloropyrimidine then drops sharply and the formation of high boilers and resins increases sharply (see Example 7).

• a) pro Äquivalent gegen Chlor ausgetauschte Hydroxylgruppen 0,75 bis 1,5 Mol Phosphortrichlorid und 0,7 bis 1,4 Mol Chlor so zufügt, daß stets ein Überschuß von Phosphortrichlorid gegenüber Chlor vorliegt und
• b) bei vermindertem Druck nacheinander Phosphoroxychlorid und das hergestellte Polychlorpyrimidin über eine Kolonne abdestilliert oder die Schritte a) und b) in umgekehrter Reihenfolge durchführt, wobei im Falle b) nach a) vor dem Phosphoroxychlorid noch Phosphortrichlorid und im Falle a) nach b) nach Durchführung des Schrittes a) erneut gebildetes Phosphoroxychlorid abdestilliert wird und
• c) den dann vorliegenden Destillationsrückstand mit einer starken Base versetzt und aus diesem Gemisch das eingesetzte tertiäre Amin wiedergewinnt, indem man
• d) die obere Phase abtrennt und
• e) destillativ reinigt
  oder die Schritte d) und e) in umgekehrter Reihenfolge durchführt.

A process has now been found for the preparation of polychloropyrimidines by reacting polyhydroxypyrimidines or their tautomeric keto compounds with excess phosphorus oxychloride in the presence of a tertiary amine, which is characterized in that after this reaction

• a) Add 0.75 to 1.5 mol of phosphorus trichloride and 0.7 to 1.4 mol of chlorine per equivalent of hydroxyl groups exchanged for chlorine so that there is always an excess of phosphorus trichloride over chlorine and
• b) successively distilling off phosphorus oxychloride and the polychloropyrimidine prepared over a column at reduced pressure or carrying out steps a) and b) in the reverse order, with phosphorus trichloride in case b) after a) before phosphorus oxychloride and after case a) after b) Carrying out step a) again formed distilled phosphorus oxychloride and
• c) the distillation residue then present is mixed with a strong base and the tertiary amine used is recovered from this mixture by
• d) separates the upper phase and
• e) cleans by distillation
  or carry out steps d) and e) in reverse order.

4,6-Dihydroxyprimidine or barbituric acid (that is the keto form of 2,4,6-trihydroxypyrimidine) is preferably used in the process according to the invention and 4,6-dichloro- or 2,4,6-trichloropyrimidine is prepared.

4,6-dihydroxypyrimidine is a known compound which is obtainable, for example, from malonic acid diamide and ethyl formate (J. Chem. Soc. 1951 , 2214). Barbituric acid, phosphorus oxychloride, phosphorus trichloride and chlorine are commercially available.

For example, 2.5 to 12 moles of phosphorus oxychloride can be used per mole of polyhydroxypyrimidine. This amount is preferably 3.5 to 5 mol when using 4,6-dihydroxypyrimidine and 4.5 to 10 mol when using barbituric acid.

Suitable tertiary amines are, for example, alkylated pyridines, alkylated imidazoles, alkylated indoles, N-dialkylated anilines and tertiary N-alkyl amines. Alkylated pyridines, alkylated imidazoles and alkylated indoles are preferred. 2-Methyl-5-ethyl-pyridine, 1,2-dimethylimidazole and 2,3,3-trimethylindolenine are particularly preferred.

Tertiary amine can e.g. use in amounts of 1 to 5 moles per mole of polyhydroxypyrimidine. This amount is preferably 1.8 to 2.2 mol when using 4,6-dihydroxypyrimidine and 2.7 to 3.5 mol when barbituric acid is used.

Temperatures in the range from 0 to 120 ° C. are suitable, for example, for the reaction of polyhydroxypyrimidines with phosphorus oxychloride in the presence of tertiary amines. Temperatures of 20 to 100 ° C. are preferred. You can e.g. proceed in such a way that phosphorus oxychloride and the polyhydroxypyrimidine are initially charged and the tertiary amine is metered in. It is advantageous to start metering at a low temperature, e.g. at 0 to 30 ° C, at a higher temperature to stop metering, e.g. at 60 to 95 ° C and for 1 to 5 hours at higher temperatures, e.g. at 80 to 105 ° C.

The procedure can also be such that phosphorus oxychloride and the tertiary amine are initially introduced and the polyhydroxypyrimidine is metered in. It is advantageous to carry out the addition at 80 to 105 ° C. and to stir at this temperature for a further 1 to 5 hours.

Other working methods and other temperatures in the range of 0 to 120 ° C are also possible.

Then, in step a), the amounts of phosphorus trichloride and chlorine given above are added to the reaction mixture in such a way that there is always an excess of phosphorus trichloride over chlorine in the reaction mixture. The excess is advantageously such that there is always 0.3 to 5% by weight, preferably 0.5 to 2% by weight, of free phosphorus trichloride in the reaction mixture. The procedure can be such that phosphorus trichloride and chlorine are metered in uniformly and with a brief specification of phosphorus trichloride. The addition of phosphorus trichloride and chlorine can e.g. at 60 to 105 ° C. After the addition of phosphorus trichloride and chlorine has ended, it is advantageous to stir at 60 to 105 ° C for some time, e.g. 10 minutes to 3 hours.

To work up the reaction mixture according to stage b), fractional distillation is first carried out on a column under reduced pressure. The pressure may initially be e.g. are between 500 and 50 mbar. The column can have, for example, 5 to 20 theoretical plates. The column can be operated, for example, with a reflux ratio of 0.8 to 5: 1. At first, any phosphorus trichloride still distilled off, this is usually only a small amount. The next fraction is phosphorus oxychloride, which, like the distilled-off phosphorus trichloride, can be reused. Then it is advantageous to adjust the pressure e.g. to be set in the range from 100 to 5 mbar and to distill off the polychloropyrimidine prepared at bottom temperatures of up to 160 to 200 ° C. You can collect this in a fraction.

If you want to obtain particularly pure polychloropyrimidine, it is advantageous to first collect a main fraction containing polychloropyrimidine with a purity of over 97%. When the condensing distillate begins to turn slightly yellow, a wake can then be collected which contains polychloropyrimidine of a purity of more than 80% and makes up about 5 to 10% by weight of the main fraction. This wake can be returned to the corresponding distillation when working up the next batch.

With the process according to the invention, depending on the tertiary amine used, polychloropyrimidines, in particular 4,6-dichloropyrimidine, can be obtained in yields of around 80 to almost 100%. With the preferred tertiary amines to be used, the yields are in the range from 95 to almost 100%.

Steps a) and b) can also be carried out in the reverse order. If one works in the order b) → a), then after step a), newly formed phosphorus oxychloride must be distilled off.

The sequence a) → b) gives a polychloropyrimidine which contains traces of phosphorus oxychloride. In the reverse order, ie b) → a), a polychloropyrimidine is obtained which contains traces of the tertiary amine. The sequences that are possible here will therefore be chosen so that a polychloropyrimidine is obtained whose impurities are the least disruptive to further processing.

Polychloropyrimidines which contain practically no further impurities can be obtained if the polychloropyrimidine distilled off in stage b) is subjected to a second distillation or the distillation is carried out as a rectification to remove the polychloropyrimidine.

The distillation residue which remains after the polychloropyrimidine has been separated off and which contains the hydrochloride of the tertiary amine used as an essential constituent is now treated with a strong base in step c). For example, concentrated aqueous solutions of alkali metal hydroxides are suitable. Based on 1 mol of tertiary amine used, e.g. 1 to 2 moles, e.g. Use 35 to 55% by weight aqueous potassium hydroxide or sodium hydroxide solutions. The strong base is preferably added to the distillation residue at temperatures at which it may, if necessary. even difficult to stir. Temperatures of 60 to 100 ° C are often suitable. The addition of the strong base can be relatively slow, e.g. in the course of 1/2 to 5 hours and with good stirring.

The upper phase is then separated off (stage d)).

Now the upper phase according to step e) is distilled again under reduced pressure. The pressure can be, for example, 100 to 10 mbar. During the distillation, stirring is preferably carried out and the bottom temperature is raised to, for example, 150 to 200 ° C. by the end of the distillation.

This distillation produces a two-phase distillate. The lower, aqueous phase generally contains only a little tertiary amine, for example below 1% by weight of the feed. The upper, organic phase contains the recovered tertiary amine, usually over 90% by weight of the amount used, in a purity of over 95%. It can after stripping of traces of water can be used again for the reaction of polyhydroxypyrimidines with phosphorus oxychloride.

During the distillation, a brown salt mass remains, which can be removed from the distillation vessel by dissolving it in water.

Steps d) and e) can also be carried out in the reverse order.

In the order d) → e) it is advantageous to introduce larger amounts of water or to use a more dilute strong base in order to obtain two liquid, solid-free, easily separable phases. This increases the amount of waste water, but you can work with simple equipment.

In the reverse order, i.e. e) → d), the strong base can also be used in a concentrated form, e.g. as 50 to 80 wt .-% aqueous potassium hydroxide or sodium hydroxide solution. This process produces less wastewater, but it requires more complicated equipment, e.g. Paddle dryer.

The process according to the invention has a number of advantages which make it particularly suitable for use on an industrial scale. The tertiary amine used can thus be recovered and reused. The yields of polychloropyrimidines, in particular 4,6-dichloropyrimidine, are almost 100% of theory when using certain tertiary amines, otherwise they are the same as or better than in known processes. The distillative work-up now possible means that much less and much easier to dispose of waste. Sublimation devices and extraction agents do not have to be handled. Not only the phosphorus oxychloride used in excess, but also the phosphorus oxychloride newly formed from phosphorus trichloride in the process according to the invention is obtained in such a pure form that it can be used as desired.

Examples example 1

2680 g of phosphorus oxychloride and 460 g of 4,6-dihydroxypyrimidine (98% strength) were mixed and 980 g of 2-methyl-5-ethyl-pyridine were metered in at room temperature in 90 minutes, with stirring. The temperature was limited to a maximum of 80 ° C by cooling. Then the mixture was stirred at 90 ° C. for 1 hour and at 100 ° C. for 1 hour. Now 1105 g of phosphorus trichloride and 570 g of chlorine were metered in simultaneously at 100 ° C. in the course of 1 hour in such a way that 25 ml of phosphorus trichloride were always present in excess in the reaction mixture compared to the chlorine introduced. The mixture was stirred at 100 ° C for 30 minutes, then a small amount of phosphorus trichloride and then 3835 g of phosphorus oxychloride were distilled off to a bottom temperature of 130 via a column with 20 theoretical plates and a reflux ratio increasing from 1: 1 to 3: 1 at 100 mbar ° C. Thereafter, the 4,6-dichloropyrimidine prepared was distilled off through a short column with 3 theoretical plates at 20 mbar to a bottom temperature of 175 ° C., 553 g of a main run (purity 98.1%; yield 91% of theory) .) and then at the start of distillation of the amine hydrochloride (slightly yellowish syrupy condensate) 41 g of a wake (purity 88%; yield 6% of theory). The overall yield of 4,6-dichloropyrimidine was therefore 97% of theory

Thereafter, 800 g of 50% strength aqueous sodium hydroxide solution were added to the viscous distillation residue at 90 ° C. over the course of 2 hours and with thorough stirring. The mixture was then distilled to dryness with vigorous stirring at 50 mbar and a bottom temperature of 170 ° C. The distillate consisted of 492 g of an aqueous lower phase, which contained 0.5% by weight of the 2-methyl-5-ethyl-pyrimidine used, and 932 g of an organic upper phase, which was 98.8% by weight of 2-methyl -5-ethyl-pyridine consisted, which corresponds to 94 wt .-% of the use. The powdery, salt-like distillation residue dissolved almost completely in water.

Example 2

2680 g of phosphorus oxychloride were introduced and 980 g of 2-methyl-5-ethyl-pyridine were added with cooling. Then 460 g of 4,6-dihydroxypyrimidine were metered in over the course of 1 hour. The further implementation and working up were carried out as described in Example 1.

4,6-dichloropyrimidine was obtained in almost 100% yield and 88% by weight of the feed was recovered from the amine.

Examples 3 to 6

The procedure was as in Example 1, but a different tertiary amine was used in each case and several batches were carried out in each case.

Example 3:

2,3,3-trimethylindolenine, yield of 4,6-dichloropyrimidine: 98 to 100% of theory

Examples 4:

1,2-dimethylimidazole, yield of 4,6-dichloropyrimidine: 97 to 99% of theory

Example 5:

N-dimethylaniline, yield of 4,6-dichloropyrimidine 78 to 88% of theory

Example 6:

Tri-n-butylamine, yield of 4,6-dichloropyrimidine 75 to 85% of theory

Example 7: (for comparison)

460 g of phosphorus oxychloride and 62 g of N, N-dimethylaniline were mixed and 116 g of 4,6-dihydroxypyrimidine (98%) were metered into the mixture at 100 ° C. in the course of 5 hours using a screw. The mixture was then stirred at 106 to 128 ° C for 8 hours. The reaction mixture was diluted with 300 g of chlorobenzene and poured onto 1.2 kg of ice. The organic phase was separated and washed twice with 100 ml of water and then fractionally distilled. 85.7 g of 4,6-dichloropyrimidine (= 58% of theory) are obtained in this way.

Example 8:

2,680 g of phosphorus oxychloride were introduced and 980 g of 2-methyl-5-ethylpyridine were added with cooling. Then 460 g of 4,6-dihydroxypyrimidine were metered in so that the temperature did not exceed 40.degree.

After half an hour of subsequent reaction at 40 to 45 ° C., first phosphorus oxychloride, then 4,6-dichloropyrimidine was distilled off, as described in Example 1.

1,390 g of phosphorus oxychloride and 595 g of 4,6-dichloropyrimidine (content 98.2%) were obtained, which corresponds to a yield of 98% of theory.

The distillation residue - essentially the dichlorophosphoric acid salt of methylethylpyridine - was reacted with 1200 g phosphorus trichloride, 600 g phosphorus oxychloride and 570 g chlorine at a temperature rising from 80 to 100 ° C. Thereafter, as described in Example 1, first 100 g of phosphorus trichloride and then 1 810 g of phosphorus oxychloride were obtained by distillation.

The viscous distillation residue was worked up as described in Example 1.

902 g of methyl ethyl pyridine were recovered (92% of the use).

Example 9:

128.0 g barbituric acid were stirred with 700 g phosphorus oxychloride. Then 242 g of 2-methyl-5-ethylpyridine were added dropwise over the course of an hour so that the temperature did not exceed 55 ° C. The mixture was then stirred for half an hour at 70, 80 and 90 ° C, whereupon the barbituric acid had practically completely dissolved. After the addition of 80 g of phosphorus trichloride, 411 g of phosphorus trichloride and 215 g of chlorine were metered in simultaneously at from 90 to 95 ° C. over the course of two hours. The mixture was subsequently refluxed at 100 ° C. for 30 minutes.

At the end of the HCl development, a small amount of phosphorus trichloride and then at 50 mbar were added to 135 g of phosphorus oxychloride up to a bottom temperature of 135 ° via a column with 20 theoretical plates and a reflux ratio of 100 mbar increasing from 1: 1 to 3: 1 C distilled off. Thereafter, 172 g of 2,4,6-trichloropyrimidine (98.1%) were distilled at 4 to 5 mbar, a bottom temperature between 96 and 140 ° C and a top temperature between 75 and 120 ° C by distillation through a 5-tray column. obtained, which corresponds to a yield of 96% of theory.

The viscous distillation residue (316 g) was worked up as described in Example 1. 226 g of methyl ethyl pyridine were recovered (93% of the use).

Claims (10)

Process for the preparation of polychloropyrimidines by reacting polyhydroxypyrimidines or their tantomeric keto compounds with excess phosphorus oxychloride in the presence of a tertiary amine, characterized in that after this reaction a) Add 0.75 to 1.5 mol of phosphorus trichloride and 0.7 to 1.4 mol of chlorine per equivalent of hydroxyl groups exchanged for chlorine so that there is always an excess of phosphorus trichloride over chlorine and b) successively distilling off phosphorus oxychloride and the polychloropyrimidine prepared over a column at reduced pressure or carrying out steps a) and b) in the reverse order, with phosphorus trichloride in case b) after a) before phosphorus oxychloride and after case a) after b) Carrying out step a) again formed distilled phosphorus oxychloride and c) the distillation residue then present is mixed with a strong base and the tertiary amine used is recovered from this mixture by d) separates the upper phase and e) cleans by distillation
or carry out steps d) and e) in reverse order. Process according to Claim 1, characterized in that 4,6-di-hydroxypyrimidine or barbituric acid is used and 4,6-dichloro- or 2,4,6-trichloropyrimidine is prepared. Process according to Claims 1 and 2, characterized in that 2.5 to 12 moles of phosphorus oxychloride are used per mole of polyhydroxypyrimidine. Process according to Claims 1 and 3, characterized in that an alkylated pyridine, an alkylated imidazole, an alkylated one is used as the tertiary amine Indole, an N-dialkylated aniline or a tertiary N-alkylamine in an amount of 1 to 5 moles per mole of polyhydroxypyrimidine. Process according to Claims 1 to 4, characterized in that the reaction of the polyhydroxypyrimidine with phosphorus oxychloride is carried out in the presence of a tertiary amine at 0 to 120 ° C and phosphorus trichloride and chlorine are added at 60 to 105 ° C. Process according to Claims 1 to 5, characterized in that the polychloropyrimidine is distilled off at 500 to 50 mbar phosphorus trichloride and phosphorus oxychloride and at pressures of 100 to 5 mbar and at bottom temperatures up to 160 to 200 ° C. Process according to Claims 1 to 6, characterized in that the phosphorus oxychloride used in excess and the newly formed phosphoroxychloride are used in any desired manner after it has been separated off. Process according to Claims 1 to 7, characterized in that the polychloropyrimidine is collected as the main fraction and as the wake. Process according to Claims 1 to 8, characterized in that a concentrated aqueous solution of alkali metal hydroxides is used as the strong base in an amount of 1 to 2 moles, based on 1 mole of tertiary amine used. Process according to Claims 1 to 9, characterized in that the tertiary amine used is distilled off at 100 to 10 mbar and bottom temperatures up to 150 to 200 ° C, and a lower aqueous phase and an upper phase containing the tertiary amine are obtained as the distillate.